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A pilot study of neoadjuvant chemotherapy with 5-fluorouracil and cisplatin with surgical resection and postoperative radiation therapy and/or chemotherapy in adenocarcinoma of the esophagus

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A pilot study of neoadjuvant chemotherapy with 5-fluorouracil and cisplatin with surgical resection and postoperative radiation therapy and/or chemotherapy in adenocarcinoma of the esophagus
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  A Pilot Study zyx f Neoadjuvant Chemotherapy With 5 Fluorouracil and Cisplatin With Surgical Resection and Postoperative Radiation Therapy andlor Chemotherapy in Adenocarcinoma of the Esophaps zyxw obert W. Carey, MD,* Alan D. Hilgenberg, MD,t Noah C. Choi, MD, Douglas J. Mathisen, MD,t Hermes C. Grillo, MD,t John C. Wain, MD,t Diana L. Logan, RN,t and Cheryl Bromberg, BA**§ Fifteen patients with potentially resectable adenocarcinoma of the esophagus were treated with two cycles of preoperative chemotherapy with 5-fluorouracil(5-FU) and cisplatin zyxwvuts DDP). esponse to chemotherapy was evaluated by comparative barium swallow, computerized chest tomography, esophagoscopy, and change in clinical symptomatology. Eleven patients (73 ) were resected, two (13 ) were explored and found inoperable, and two (13 ) were not subjected to surgery (one because of death related to toxicity and one due to progressive disease). Ten of eleven patients (91 ) had gross residual tumor. One patient (9 ) had residual microscopic disease only. One patient (7 ) had complete clinical response (CCR), five (33 ) had partial clinical response (PCR), and nine (60 ) had no response (NR). Five of 15 patients [or 45 of resected patients) remain free of disease. Median survival time was 18.47 months for all patients and 23.83 months for resected patients. Cancer 68:489-492,1991. DENOCARCINOMA OF THE ESOPHAGUS is increasing zyxwv   in frequency. zyxwvut ,2 Overall prognosis has been In a recent investigation at Massachusetts General zyxwv os- pital (Boston, Massachusetts), the overall 5-year survival rate after resection alone was 23%, and patients with T3NlMO (Stage 111) had only an 1 1% survival rate.4 Many investigations have documented the use of neoadjuvant chemotherapy in squamous cell carcinoma of the esophagus.5-' Studies indicate a high response rate to chemotherapy and suggest improved survi~al.~~'~ It is unclear whether adenocarcinoma and squamous cell carcinoma of the esophagus are comparable in biology or outcome. The literature has been confusing because From *Medical Services, tSurgical Services, and the $Department of Radiation Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and the §Albany Medical College, Albany, New York. Supported by the Sundry Fund for Medical Oncology, Massachusetts General Hospital. Address for reprints: Robert W. Carey, MD, Massachusetts General Hospital, 100 Blossom Street/Cox 2, Boston, Massachusetts. Accepted for publication May I 199 1. many studies have assessed patients with adenocarcinoma and patients with squamous cell carcinoma together.',' We evaluate each patient group separately and currently report the experience of adenocarcinoma of the esophagus in 15 patients. The experimental regimen used is the same one that has shown increased survival rates in patients with squamous cell carcin~ma.~~'~ Materials and Methods zy atient Selection and Evaluation Patients with potentially resectable and histologically proven adenocarcinoma of any portion of the esophagus with localized disease were eligible. One hundred percent of the patients in this series, however, had distal lesions of the lower y3 of the esophagus and/or gastroesophageal junction. Patients were ineligible if distant metastases were documented. Patients were required to have a Cancer and Leukemia Group B performance status of 2 or greater, adequate renal function (serum creatinine less than 1.4 mg/dl, creatinine clearance of 60 ml/min or greater), and 489  490 CANCER zyxwv ugust 199 1 Vol. z 8 quate hematologic function (granulocyte count more than 4000/p1, platelet count more than lOO,OOO/pl). Signed in- formed consent was obtained from all patients. Staging of patients included baseline computed tomography (CT) of the chest and upper abdomen, barium swallow, and endoscopic biopsy. Demographic Data From September 1987 to September 1989, 15 patients entered this study. All patients were evaluated in this dis- cussion. Median age was 63 years of age (range, 35 to 75 years of age). Twelve patients (80%) were men and three patients (20 ) were women. Thirteen patients (87 ) had a history of tobacco use, 12 (80 ) had a history of excessive alcohol consumption, and 11 (73 ) had a history ofboth. Two patients zyxwvuts 1 3 ) had a history of peptic ulcer disease, and two zyxwvutsr   13 ) had a history of heartburn. Two patients 13 ) had a history of severe hiatal hernia, and four (27 ) had esophageal reflux. Twelve patients (80%) noted dys- phagia for an average duration of 12.25 months. Eight patients (53 ) had significant weight loss (average loss, 6.5 kg). Barrett’s esophagus was found in 5 patients (45 ) of 11 resected patients. Follow-up was obtained on 15 patients. Study Design The objectives of this study were to ascertain the efficacy of 5-fluorouracil(5-FU) and cisplatin (DDP) in achieving regression of adenocarcinoma of the esophagus and as- sessing survival of patients treated on the program. Post- operative radiation therapy was limited to patients with direct invasion of mediastinal structures, metastases to thoracic or abdominal lymph nodes, or positive resection margins. Postoperative chemotherapy was recommended to patients with complete or partial clinical response to preoperative chemotherapy. Chemotherapy Chemotherapy consisted of 5-FU (1000 mg/m2) by 24- hour infusion for 4 days in a volume of 2000 ml normal saline per day. To minimize phlebitis related to infusion, 50 mg of Solu-Cortef (hydrocortisone sodium succinate; Upjohn Co., Kalamazoo, MI) per 1000 ml saline was added. On day 3 of hospitalization, patients were hydrated by increasing intravenous fluids with 0.45 normal saline and 5 dextrose to a total infusion rate of I50 ml/hr. On day 4, patients received bolus administration of DDP (100 mg/m2). DDP was preceded by 12.5 g of man- nitol as an intravenous bolus and was followed by an in- fusion of 20 mannitol, 0 to 5 g/hr as required to maintain urine output at 100 ml/hr for 6 hours after DDP admin- istration. Two cycles of chemotherapy were given 4 weeks apart. Complete blood counts, differential counts, platelet counts, serum creatinine, blood urea nitrogen (BUN), serum glutamic oxaloacetic transaminase SGOT), bili- rubin, alkaline phosphatase, and calcium were monitored with each course. Surgery On approximately day 56, with complete recovery from the second cycle of chemotherapy, surgical resection was performed by either left thoracoabdominal or Ivor Lewis esophagogastrectomy. The esophagus, proximal stomach, and adjacent lymph nodes were resected. Reconstruction was performed by intrathoracic esophagogastric anasto- mosis. Response Criteria Barium swallow, CT of chest and abdomen, esopha- goscopy, and blood tests were repeated after the second course of chemotherapy before surgery. After restaging studies and inspection at surgery, patients were categorized into one of three clinical responses. Complete clinical re- sponse (CCR) was classified as the resolution of dysphagia, no gross evidence of persistent tumor by radiologic or endoscopic evaluation and by surgical inspection of tumor site. Partial clinical response (PCR) was classified as a subjective decrease in dysphagia with radiologic, endo- scopic, and surgical evidence of more than 50 tumor regression. No response (NR) was classified as no change in tumor size with stable dysphagia. Postoperative Radiation Therapy Postoperative radiation therapy was administered to patients with metastatic involvement of regional lymph nodes and/or positive resection margins. Radiation target volume included tumor bed and regional lymph nodes in the mediastinum and upper abdomen, extending from the thoracic inlet to the level of the second lumbar ver- tebra. A total dose of 5400 cGy was planned over 6 weeks using daily fractions of 180 cGy, 5 dlwk. Radiation energy consisted of 10 meV photons from an 18-meV linear ac- celerator. To protect the heart, spinal cord, and large vol- ume of lung from potential radiation-related injury, a combination of multiple radiation portals was used (an- teroposterior-posteroanterior parallel opposed portals for the initial 3600 cGy, right and left posterior oblique portals for the next 1260 cGy, and then right and left lateral op- posed portals for the final 540 cGy for the total dose of 5400 cGy). Radiation therapy was started 4 to 6 weeks after surgery. Postoperative Chemotherapy Four cycles of 5-FU/DDP were recommended for pa- tients with a CCR or a PCR to preoperative chemotherapy.  No. zyxwvutsrqpo   Results NEOADJUVANT HEMOTHERAPY zyxw arey et zyx l. 49 1 Surgery Eleven patients (73 ) were resected. Esophagogastrec- tomy was performed in nine patients (82 ) by left thora- coabdominal resection and in two patients z   18 ) by Ivor Lewis resection (abdominal and right thoracic incisions). Exploration alone was performed on two patients (1 3 ) due to intraoperative detection of peritoneal metastases. Two patients 13 ) did not receive surgery after chemo- therapy (one patient died after cycle 1 of treatment, and results of a repeat CT in the second patient showed liver metastases and unresectable disease). Postoperative complications included one patient with atrial fibrillation and one patient with fever of unknown srcin that spontaneously resolved. Pulmonary emboli- zation occurred in two patients, resulting in death in one patient and the placement of an inferior vena caval filter in the other. There were no anastomotic leaks. Response to Chemotherapy One patient (7 ) had a CCR, five (33 ) had a PCR, and nine (60 ) had NR to chemotherapy. Three patients with NR did not complete preoperative chemotherapy. The first patient received only one cycle due to superficial phlebitis of the lower legs. Results of a repeat CT scan and barium swallow of a second patient after the first cycle showed near complete obstruction of the distal third of the esophagus, and the aorta was totally surrounded by tumor: also, liver metastases and severe adenopathy were documented. Extent of disease precluded surgical treatment. A third patient died after cycle 1 with bron- chopneumonia, sepsis, coagulopathy, and pancytopenia. This was a presumed toxic death. Chemotherapy Toxicity Nephrotoxicity Nephrotoxicity was evaluated in 1 5 patients. Fourteen patients had serum creatinine values less than 1.4 mg/dl (range, 0.7 to 1.4). DDP dose adjust- ment was not required. One patient died of sepsis and pancytopenia after cycle 1 with serum creatinine values of 1.7 (day 7 after the start of chemotherapy) and 2.0 (day 16 after start of chemotherapy [day of death]). Hematologic toxicity Hematologic toxicity was assessed in each of 12 patients receiving two cycles of chemother- apy. All patients received treatment as scheduled per pro- tocol. Normal blood counts were present at the start of each cycle for all patients. Nadir counts were not available in two patients. In nine of ten nadir results evaluated, the leukocyte count was more than 4,0OO/p1. The lowest nadir count was 3,00O/pl. Of those patients receiving two cycles of chemotherapy, none had infection. As noted previously, one patient died of sepsis and pancytopenia with platelet counts ranging from 8000 to 41,OOO/pl during days 8 through 16. Leukocyte counts ranged from 3000 to 0.3/pl during days 9 through 16 in this patient. One patient with a hematocrit of 23.8 required trans- fusion of two units at the start of treatment. Hematocrit was raised to 33.0 Gastrointestinal toxicity Eleven patients (73 ) noted gastrointestinal difficulty. Complaints of mild nausea, emesis, and diarrhea were most frequent. One patient had severe nausea and vomiting for which an additional day of hospitalization was required. All patients were given anti-emetic medication in conjunction with chemother- apy. One patient (7 ) complained of severe mouth ulcers after the second cycle of chemotherapy. Other toxicity Two patients zyxwvu 1 3 ) noted chemical phlebitis, although hydrocortisone was used with the zyxw -FU nfusion. Pathology Of the 1 1 resected patients, 10 (9 1%) had gross evidence of tumor. One patient (9 ) showed no gross evidence although microscopic tumor was found. Foreign body giant cell reactions were not present. Barrett's esophagus was found in five patients (45 ). Invasive tumor was present in 10 patients (9 1 ). One patient (9 ) had disease approaching but not invading the muscularis propria. Tumor stage included TI in one patient (9 ), T2 in 4 (36 ), and T3 in 6 zyx 55%). Lymph nodes were positive for tumor in nine patients (82 ) (range, 1 to 10 positive/ 10 to 34 nodes examined). Resection margins were pos- itive for tumor in three patients (27 ) (one [9 ] with positive proximal margins and two [ 18 ] with positive deep margins). Distant metastases were not evident. Postoperative Radiation Therapy Ten of 15 patients (66 ) eceived postoperative radia- tion therapy. The median dose was 5389 cGy (range, 4500 to 5600 cGy). 100 zyxwv P h I I 20 i 0 0 6 12 18 24 30 36 42 Time (months) Median Survival Time 18.47 Months FIG. 1. Survival of all I5 patients treated on protocol.  492 CANCER ugust zyxwv   199 1 Vol. 68 z 40 - V zyxwvutsrqponmlkjihgfedcb   I , zyxwvutsr 0 - Postoperative Chemotherapy Four of ten patients who received postoperative radia- tion therapy zyxwvutsr 40 ) also received postoperative chemo- therapy (27 of all patients). Survival Survival of all patients is shown in Figure 1 (median, 18.47 months). Survival of resected patients in shown Figure 2 (median, 23.83 months). Conclusion There was evidence of anti-tumor response to 5-FU and DDP, including one CCR and five PCR of 15 patients (40 esponse rate). Five of eleven patients completing surgery (45%) cur- rently have no evidence of disease. It is too early to assess the effect of chemotherapy on survival in this study. In our experience with resected pa- tients with squamous cell carcinoma of the esophagus, a 5-year survival rate of 39% compares with a historical control rate of 2 1 ,9 but only complete response to che- motherapy is associated with prolonged survival. Even with this remarkable increase in survival of squamous cell carcinoma observation in a single institution, a prospective randomized clinical trial is essential to establish the true role of neoadjuvant chemotherapy. Such a trial is now being performed in a prospective randomized fashion through the intergroup mechanism.'* In adenocarcinoma of the esophagus, the evidence to date for the role of chemotherapy in treatment is much less compelling. However, we are encouraged that we have documented some clinical responses. Response rates for higher stage adenocarcinoma are even worse. Patients with Stage 111 disease and postoperative adjuvant therapies have a 5-year survival rate of 1 Our results are similar to those of Ajani et a1.13 who studied neoadjuvant chemotherapy with etoposide, 5-FU, zyxwv S zyxwvutsrqp 0 1 0 6 12 10 24 30 36 42 Time months) Median Survival Time = 23.83 Months FIG. 2. Survival of all 1 1 patients completing esophageal resection. and DDP in adenocarcinoma of the esophagus. Major responses occurred in 49% of patients, and one pathologic complete response was found. With a median follow-up time of 20 months, a projected survival time of 23 months was reported. Also currently under study is the combination of Adriamycin (Adria Laboratories, Columbus, OH)/DDP/ etoposide with granulocyte-macrophage colony-stimulat- ing factor (GM-CSF). Acceptable toxic effects have been noted, although response data have not yet been pub- 1i~hed.I~ ontrolled prospective clinical trials of adeno- carcinoma of the esophagus may be desirable. The search for active treatment programs with the capacity to achieve tumor regression at tolerable toxicity should continue. REFERENCES 1. Hesketh PJ, Clapp RW, Doos WG, Speckler ST. The increasing frequency of adenocarcinoma of the esophagus. Cancer 1989; 64:526- 530. 2. Kalish RJ, Clancy PE, Omnger MB et al Clinical epidemiologic and morphologic comparison between adenocarcinoma arising in Bar- rett's esophagus mucosa and in the gastric cardia. Gastroenterology 1984; 3. Silverberg E, Lubera JA. Cancer statistics, 1989. Cancer 1989; 39: 4. Schwartz L, Choi NC, Carey RW, Grillo HC, Mester M, Convery K. Adenocarcinoma of the esophagogastric unction: Evaluation of post- operative adjuvant therapy. Int J Radial Oncol iol Phys (in press). 5. Carey RW, Hilgenberg AD, Wilkins EW, Choi NC, Mathisen DJ, Grillo HC. Preoperative chemotherapy followed by surgery with possible postoperative radiotherapy in squamous cell carcinoma of the esophagus: Evaluation of the chemotherapy component. J zyx lin Oncoll986; 4:697- 701. 6. Leichman L, Steiger Z, Seydel HG ef zyx / Preoperative chemotherapy and radiation therapy for patients with cancer of the esophagus: A po- tentially curable approach. J CIin Oncol 1984; 2:75-79. 7. Forastiere A, Gennis M, Omnger M, Agha FP. Cisplatin, vinblas- tine, and mitoguazone chemotherapy for epidermoid and adenocarci- noma of the esophagus. J Clin Oncol 1987; 5:1143-I 149. 8. Omnger M, Forastiere A, Perez-Tamayo C, Urba S Takasugi BJ, Bromberg J. Chemotherapy and radiation therapy before transhiatal esophagectomy for esophageal cancer. Ann Thorac Surg 1990; 49:348- 355. 9. Carey RW, Hilgenberg AD, Grillo HC, Mathisen DJ, Choi NC, Logan DL. Esophageal Carcinoma: Long term follow up of patients treated by neoadjuvant chemotherapy, surgery and possible postoperative radiation and/or chemotherapy (Abstr). Proc Am Soc Clin Oncol 1990; 105. 10. Hilgenberg AD, Carey RW, Wilkins EW, Choi NC, Mathisen DJ, Grill0 HC. Preoperative chemotherapy, surgical resection, and selective postoperative therapy for squamous cell carcinoma of the esophagus. 4nn Thorac Surg 1988; 43:357-363. 1. Beahrs OH, Henson DE, Hutter RVP, Meyers MH, eds. Manual for Staging of Cancer, ed. 3. Philadelphia: J. B. Lippincott, 1988; 63- 65. 12. Kelsen D, Ginsberg R, Minsky B. A phase I Intergroup trial: A prospective randomized comparison of combined modality therapy for carcinoma of the esophagus. Chemotherapy plus surgery versus surgery alone for patients with local regional disease. A Radiation Therapy On- cology Group protocol (RTOG #89- 1 1 ). 13. Ajani JA, Roth JA, Ryan B ef a/. Evaluation of pre- and post- operative chemotherapy for resectable adenocarcinoma of the esophagus or gastroesophageal junction. J Clin Oncol 1990; 8:1231-1238. 14. Ajani JA, Roth JA, Ryan B e/ al Feasibility and toxicities ofGM- CSF given with high-dose chemotherapy for resectable adenocarcinoma of the esophagus (Abstr). Proc Am Soc Clin Oncol 1990; 9. 86~461-467. 3-20.
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